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3: Glucocorticoid, Mineralocorticoid, and Immunomodulatory Agents
DOI: 10.2337/9781580406192.03
Glucocorticoid Steroids
In people with diabetes, systemic glucocorticoid steroid therapy impairs glycemic control via multiple mechanisms. Glucocorticoids induce insulin resistance, inhibit peripheral glucose utilization, stimulate lipolysis, and increase hepatic glucose production.1–3 In addition, these steroids inhibit insulin secretion and insulin biosynthesis, stimulate glucagon release, and induce endoplasmic reticulum stress and β-cell apoptosis following prolonged exposure (Figure 3.1).2,4–6 In people with prediabetes and those at high risk for type 2 diabetes (T2D), prolonged steroid therapy could worsen glucose tolerance and induce diabetes. There is significant heterogeneity in individual susceptibility to glucocorticoid-induced dysglycemia. Accurate data on the exact magnitude of risk are lacking, and the tendency to report mostly fasting glucose levels might mask the true prevalence of the problem.
Figure 3.1—Constellation of the diabetogenic actions of glucocorticoids. ER, endoplasmic reticulum.
In one nested case control study based on a family practice database, the adjusted odds ratio for diabetes associated with three or more oral glucocorticoid prescriptions was 1.36 (95% confidence interval [CI] 1.10–1.69; P = 0.005).7 Thus, the risk of treatment-emergent diabetes was increased by 36% following oral steroid exposure.7 The diabetes risk is dependent on the dose and duration of glucocorticoid therapy, but even single doses of potent agents, such as dexamethasone, can induce transient hyperglycemia.8 Genetic factors play a prominent role in determining susceptibility: in one study, a family history of diabetes increased the risk of steroid-induced diabetes tenfold.9 Other risk factors for steroid-induced diabetes include the potency of steroid preparation, age, weight, decreased β-cell capacity, and a history of gestational diabetes (Table 3.1).10,11 Compared with systemic therapy, inhaled or topical glucocorticoids or glucocorticoid eye drops have not been consistently associated with hyperglycemia.6,7,12
Table 3.1—Risk Factors for Steroid-Induced Diabetes
• Family history of diabetes
• Type, dose, and duration of steroid therapy
• History of gestational diabetes
• Overweight or obesity
• Older age
• Decreased insulin secretory capacity
High doses of topical steroids, however, can sometimes induce hyperglycemia.10 Reports are conflicting on the effects of intra-articular steroid injection on blood glucose levels.13–15 Overall, the reported glucose excursions tend to be transient, returning to baseline within a few hours to 5 days following the injection of steroids into inflamed joints.15,16
Approach to Risk Reduction
When systemic glucocorticoid therapy is unavoidable, as in patients with acute severe asthma or transplant recipients, blood glucose levels should be monitored frequently and the antidiabetic regimen should be optimized. Insulin sensitizer drugs and insulin augmentation, alone or in combination, can help restore glycemic control in most patients with steroid-induced diabetes.17 Because the metabolic effects of glucocorticoids are dose related, use of the minimum effective dose for treatment of the primary condition is recommended. For people with prediabetes and those at high risk for T2D, lifestyle modification (Table 3.2) has been shown to be effective in preventing diabetes and should be advocated empirically, although there are no specific data for the steroid-treated population. In experimental animals, treatment with etomoxir (an inhibitor of fatty acid oxidation) improves insulin sensitivity and reverses glucocorticoid-induced insulin resistance.18
Table 3.2—Approach to Prevention of Glucocorticoid-Induced Diabetes
• Identify risk factors for diabetes (age, family history, overweight/obesity, etc.)
• Monitor blood glucose frequently in high-risk subjects
• Recommend lifestyle modification for high-risk people
• Use minimum effective dose of glucocorticoid steroid
• Consider alternate-day regimen, if feasible
• Consider metformin for people with prediabetes (impaired fasting glucose and impaired glucose tolerance)
The possible prophylactic use of insulin sensitizers (e.g., thiazolidinediones [TZDs] and metformin) to prevent diabetes during